HER2 oncoprotein is overexpressed in 15-20% of breast carcinomas and is associated with poor outcome. The 2+ group is considered equivocal, since gene amplification is observed in some but not others. The aim of our study is to ascertain if there is clinical significance to heterogeneity of HER2 immunohistologic expression in breast core-needle biopsies vs surgical resection specimens. A total of 37 invasive breast carcinomas diagnosed on core-needle biopsies and scored 2+ by HER2 immunohistochemical assay were selected from our files. The results were obtained on these selected cases, of which 19 cases were nonamplified and 18 cases were amplified. The follow-up resection specimens were reviewed and two additional tumor blocks were selected in each case for HER2 immunostaining. The 74 tissue blocks were examined for HER2 using antibody clone CB11 on the Benchmark XT and scored as negative (score 0 or 1+), weakly positive (2+) or strongly positive (3+). Results within the amplified group, 56% (11/18) showed significant areas with 3+ score in both blocks, 28% (5/18) remained as 2+, 11% (2/18) showed score 0-1+. In the nonamplified group, 42% (8/19) had score 0-1+, 37% (7/19) remained as 2+, 0% (0/19) had score 3+. Five (5) cases showed heterogeneous staining in both the groups. In the amplified group, 56% of cases showed strong 3+ in both the blocks of which half of these cases had areas of 2+. Fluorescence in situ hybridization was performed on a representative resection specimen block. In the amplified group 72% (13/18) cases were amplified, 22% (4/18) were nonamplified. In the nonamplified group, no amplification is detected in a great majority of cases 89% (17/19). HER2 immunohistochemistry on core-needle biopsies is usually predictive of tumor HER2 status. However, performing fluorescence in situ hybridization on core-needle biopsies almost completely resolves the issue of heterogeneous expression of HER2.